MICA: Determining the therapeutic potential of targeting the free fatty acid receptors FFA1 and FFA4 in human lung inflammatory disease

Asthma is a chronic lung inflammatory disease that affects >300 million people worldwide, causing substantial morbidity and exacting a considerable cost to health services. Despite the effectiveness of current therapies still ~45% of asthmatics remain uncontrolled. Here we propose to investigate a novel way of treating asthma by raising drugs that activate receptor proteins that we have found are present in human lungs and that when activated can reduce inflammation and relax the airways allowing more air to get in and out of the lungs. These receptor proteins are normally activated by fatty acids such as omega-3 fatty acids that are found in our diet. It is somewhat surprising that receptor proteins that respond to dietary fatty acids are present in our lungs but we have found that this is indeed the case. We have also found that activation of these receptor proteins, called FFA1 and FFA4, can relieve many of the symptoms associated with inflammatory lung disease in mouse disease models that we have established. Here we will work together with our clinical colleagues who have access to normal human and diseased lung samples. Alongside additional studies that will take advantage of our expertise in mouse models of inflammatory lung disease we will assess if making drugs that activate FFA1 and FFA4 might potentially relieve symptoms and reduce inflammation in lung diseases such as asthma.

We have an extensive array of reagents and approaches that will be employed in the following ways

Palate of FFA1 and FFA4 pharmacological tool compounds
Available to this programme are an array of FFA1 and FFA4 selective and dual FFA1/FFA4 ligands.

Human tissue/cells.
Through our clinical PI, Prof. Chris Brightling, we have access to an extensive bio-bank of clinically curated lung biopsies from normal and asthmatic patients as well as fresh biopsies that will be gathered from patient donors during this study. We also have frozen primary human bronchial epithelial cells from patients with varying degrees of disease severity and access to human sputum samples, human lung lavage and resected lung. Furthermore, Prof. Brightling is a leader in a number of network projects through which we will gain access to patient data that can be mined specifically to address questions regarding FFA1/FFA4 function in the lung.

Mouse disease and genetic models
We have established in vivo murine lung function techniques and have established ozone pollution models (both acute and chronic exposure) and allergen inflammatory disease models. By employing these techniques in our genetic models that include FFA1 and FFA4 knockout mice and a mouse line that is uncoupled from receptor phosphorylation/arrestin-dependent signalling we will test the effects of an array of FFA1 and FFA1 pharmacological ligands to determine the mechanism of action of these long chain fatty acid receptors in the modulation of bronchoconstriction and normalisation of inflammatory airway disease.

Drug discovery platform
To meet the need for improved FFA4 ligands to take to human trials we will work in collaboration with our industrial partner Keltic Pharma Therapeutics Ltd to employ a novel cyclic-peptide based drug discovery platform to generate FFA4 ligands designed to be employed, alongside already available FFA1 ligands, in subsequently funded proof of principle human clinical trials.